Bioluminescence with a longer-wavelength and lower-energy emission is of significant interest both for multiplexing applications with multiple emission colors and for in-depth tissue imaging where shorter wavelengths tend to be strongly absorbed. Many standard systems for optical imaging have limited utility in a whole-animal context due to the diminished transmission of light through biological samples. Light penetration is limited by the absorption coefficients of particular components in blood. Strong absorption by Hemoglobin (Hb) and oxygenated hemoglobin (HbO2) diminish transmission (and penetration depth) of light through blood and animal tissues. Luminescent systems that emit light in the far red and near infrared region (680-900 nm) allow for optimal imaging due to a minimum in absorbance spectrums of Hb and HbO2. This region of maximum light penetration is known as the whole animal “optical window”. Bioluminescent reporter systems have been used extensively in research animals, yet still suffer from the limitations of diminished tissue penetration. Typical bioluminescent light emission wavelengths (460-620 nm) occur in a region with limited penetration depth. The ideal bioluminescent reporter systems in whole animals would benefit greatly from the bright light emission in the region of 680-900 nm. While numerous bioluminescent systems have been modified to shift visible light emission toward the red, none has achieved strong emission red enough to overlap significantly with the critical “optical window” of blood transmittance.